The bacterial cell envelope is the first and major line of defense against threats from the environment. It is also the target of numerous antimicrobial substances, many of which function to inhibit the growth of competitors. Resistance against antibiotics is therefore crucial for bacteria to live in a complex biosphere, such as a soil ecosystem. Sensing the presence of harmful compounds and transmitting this information to allow a quick adaptational response is the first and most important step to ensure survival.
Antibiotics that act on the cell envelope, such as vancomycin, bacitracin, nisin, and ramoplanin, trigger global stress responses coordinated by Extracytoplasmic Function (ECF) σ factors (σW and σM) and two-component regulatory systems. Some of the genes that are induced by antibiotic stress play a direct role in antibiotic resistance, a growing problem among Gram-positive pathogens.
The Extracytoplasmic Function (ECF) σ factors are small regulatory proteins that are quite divergent in sequence relative to most other a factors and form a phylogenetic distinct group within the σ70-family. They often recognize promoter elements with an “AAC” motif in the −35 region. In many cases the ECF σ factor is co-transcribed with a downstream gene, which encodes a transmembrane anti-σ factor. Most of the known systems control functions associated with some aspects of the cell surface or transport.
The genome of Bacillus subtilis contains seven ECF σ factors. The regulons of σW, σM and σX have been identified, linking their functions to antibiotic stress response, general cell envelope stress and maintenance of cell envelope net charge, respectively. Two antibiotic resistance determinants have also been described previously. The fosfomycin resistance gene fosB is controlled by σW, and the bacitracin resistance gene bcrC is under the dual control of σM and σX.
The two-component regulatory systems also play a major role in bacterial responses to antibiotics. Each two-component system is located next to target genes that are strongly induced by putative antibiotics that interfere with the lipid II cycle in the cytoplasmic membrane (such as bacitracin, vancomysin, nisin and ramoplanin). When an antibiotic is applied to a bacterial organism, a biochemical cascade of events is triggered. These events can render bacterial resistance to antibiotics.
Currently there exists a need to understand systems that are induced by putative antibiotics in order to provide insights into the mechanism of action.